Rheumatoid arthritis is a chronic, systemic, progressive autoimmune disease of unknown origin, which causes arthralgia (arthrosynovitis). In Japan, about 700,000 or more people suffer from the disease. Rheumatoid arthritis develops in people of any age, and more frequently develops in people who are in their thirties to fifties.
Genetic predisposition and environmental factors are presumably involved in the development of rheumatoid arthritis, but the etiology of rheumatoid arthritis remains unknown. Rheumatoid arthritis is a systemic disease in which CD4+ cells out of lymphocytes play a central role, and the pathology of rheumatoid arthritis includes the infiltration of inflammatory cells such as neutrophils, lymphocytes, and macrophages into the joint and the inflammatory abnormal growth of synovial cells in the joint in association with the infiltration, the subsequent development of cartilage destruction and bone erosion, and final joint structure destruction.
A diagnosis marker for rheumatoid arthritis is, for example, rheumatoid factor (RF), matrix metalloprotease-3 (MMP-3), or anti-cyclic citrullinated peptide antibody (anti-CCP antibody). The anti-CCP antibody is a serum diagnosis marker for rheumatoid arthritis, which has been developed in recent years. The antibody is said to be an excellent diagnosis method for rheumatoid arthritis as compared to a conventional diagnosis method, but is not a sufficiently satisfactory diagnosis method. In particular, rheumatoid arthritis is difficult to be diagnosed accurately at the early stage of the development. Thus, the importance of diagnosing rheumatoid arthritis at the early stage of the development and starting the treatment of rheumatoid arthritis at an earlier stage has been increasingly recognized.
Rheumatoid arthritis, the main symptom of which is polyarthralgia, is an inflammatory disease of unspecified origin. The progression of the pathology of rheumatoid arthritis is accompanied by the inflammatory infiltration of the synovial membrane, the growth and stratification of synovial cells, and angiogenesis. In particular, the abnormal growth or activation of synovial cells is thought to be one of the main lesions of rheumatism (Harriset et al., 1990, N. Eng. J. Med. 332, 1277-1289). When an investigation is made on the joint of patients with rheumatism, the growth of synovial villi, the multistratification of synovial tissue cells, and the like are observed, which suggests the abnormal growth of synovial cells. However, the cause of such hyperfunctions of synovial cells, which play important roles in forming the pathology of rheumatoid arthritis, has not been sufficiently elucidated yet, and the inhibition of the abnormal growth of synovial cells is conceivable to be extremely important in the treatment of rheumatoid arthritis.
A conventional treatment with an anti-rheumatic drug cannot completely inhibit the progression of arthritis, and there are many cases in each of which the treatment has no effect. Further, a biological formulation (anti-TNFα antibody), which has been developed in recent years, also has many problems. For example, there are cases in each of which the biological formulation has no effect or has a reduced effect, and high treatment costs are required. Accordingly, it is medically and socially important to clarify the etiology of rheumatoid arthritis and develop novel methods for diagnosis and treatment of rheumatoid arthritis.
Along with the elucidation of the genetic information of living organisms, it has been revealed that the ratio of non-coding DNA which does not encode for a protein is very high in higher living organisms. The non-coding DNA is said to account for 98.3% of the total DNA in humans. Further, as RNA is estimated to be transcribed from two-thirds of the total genome in humans, the kinds and amount of non-coding RNAs are estimated to increase depending on the complexity of biological species, and microRNA (hereinafter referred to as “miRNA”) has been discovered as one of the non-coding RNAs. The miRNA is a generic name for the non-coding RNAs having 18 to 22 bases, and about one-third of human genes are thought to be regulated by the miRNA. Various reports have already been made on the processing of the miRNA. The miRNA is expressed and highly conserved in eukaryotes. About 1000 kinds of miRNAs are estimated to exist in humans. With regard to the miRNA, JP 2006-510372 A (Patent Document 1) discloses a detection method for a low molecular nucleic acid.
The miRNA plays an important role in regulating the expression of genes. The miRNA is transcribed as pri-miRNA from DNA in the nucleus to be processed into hairpin double-stranded RNA (dsRNA) precursor. dsRNA is translocated to the cytoplasm and undergoes an action of Dicer to produce mature miRNA. The produced miRNA is incorporated into an RNA-induced silencing complex (RISC) and is involved in the regulation of gene function. The miRNA has a very similar action to that of RNA interference (RNAi) or the like, but many of the actions are unclear. For example, the RNAi inhibits translation by cleaving a target RNA, whereas most of the miRNAs are thought to inhibit translation without cleaving the target RNA. Further, there are reports that the miRNA may be involved in, for example, development, differentiation, cell cycles, and cancer diseases, and it has been revealed that each of tumor types can be distinguished from a normal sample based on specific miRNA in tumor tissues of patients with, for example, lung cancer, colon cancer, thoracic cancer, prostate cancer, bladder cancer, and pancreas cancer (Patent Document 2).
However, with regard to the miRNA, there are little reports on an immune system and an autoimmune disease, and there are no reports on rheumatoid arthritis at present.    Patent Document 1: JP 2006-510372 A    Patent Document 2: JP 2008-511678 A